Cerebral metabolism was studied in relation to age and drug responses in unanesthetized animals. Local cerebral glucose utilization (LCGU), as measured with 14C-2-deoxy-D-glucose, increased during brain growth in the Fischer-344 rat, and declined during adulthood in the Fischer-344 rat until midlife, without subsequent decrements. In the beagle, LCGU decreased progressively throughout the lifespan, but most of the significant decrements had occurred by mid-life. In the Fischer-344 rat, regional cerebral blood flow (rCBF), measured with 14C-iodoantipyrine, was not elevated by immobilization. rCBF rose during development and declined in some regions after 12 months of age. However, the cerebral metabolic rates for 02, glucose and C02, which reflect cerebral cortical oxidative metabolism, did not decline significantly between 3 and 24 months of age. 2) As retinal degeneration progressed with age and light exposure in the albino rat, a loss of photoreceptor cells was correlated with a decline in retinal glucose utilization. 3) In adult rats, central muscarinic stimulation with oxotremorine increased LCGU in areas involved in motor and cognitive function. GABA agonists generally decreased LCGU, but produced a relative increase in the dentato-rubro-thalamic pathway. 4) Fatty acid uptake by the brain was examined quantitatively.